dbSNP rs10849441: PLEKHG6:c.1525-23A>G (chr12-6326405-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001384598.1(PLEKHG6):c.1525-23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,589,732 control chromosomes in the GnomAD database, including 166,781 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.40 ( 12926 hom., cov: 32)

Exomes 𝑓: 0.46 ( 153855 hom. )

Consequence

PLEKHG6
NM_001384598.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.255

Publications

14 publications found

Variant links:

Genes affected

PLEKHG6 (HGNC:25562): (pleckstrin homology and RhoGEF domain containing G6) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Located in cell junction and centrosome. [provided by Alliance of Genome Resources, Apr 2022]

PLEKHG6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG6	NM_001384598.1 link	c.1525-23A>G		intron_variant	Intron 13 of 15	ENST00000684764.1	NP_001371527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG6	ENST00000684764.1 link	c.1525-23A>G		intron_variant	Intron 13 of 15		NM_001384598.1	ENSP00000506982.1

Frequencies

GnomAD3 genomes

AF:

0.397

AC:

60251

AN:

151694

Hom.:

12919

Cov.:

show subpopulations

Gnomad AFR

AF:

0.246

Gnomad AMI

AF:

0.404

Gnomad AMR

AF:

0.364

Gnomad ASJ

AF:

0.411

Gnomad EAS

AF:

0.262

Gnomad SAS

AF:

0.324

Gnomad FIN

AF:

0.582

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.484

Gnomad OTH

AF:

0.378

GnomAD2 exomes

AF:

0.414

AC:

102975

AN:

248920

AF XY:

0.417

show subpopulations

Gnomad AFR exome

AF:

0.254

Gnomad AMR exome

AF:

0.333

Gnomad ASJ exome

AF:

0.406

Gnomad EAS exome

AF:

0.254

Gnomad FIN exome

AF:

0.572

Gnomad NFE exome

AF:

0.478

Gnomad OTH exome

AF:

0.428

GnomAD4 exome

AF:

0.456

AC:

655064

AN:

1437920

Hom.:

153855

Cov.:

AF XY:

0.454

AC XY:

325359

AN XY:

716776

show subpopulations

African (AFR)

AF:

0.238

AC:

7877

AN:

33056

American (AMR)

AF:

0.332

AC:

14764

AN:

44460

Ashkenazi Jewish (ASJ)

AF:

0.403

AC:

10469

AN:

25966

East Asian (EAS)

AF:

0.279

AC:

11030

AN:

39516

South Asian (SAS)

AF:

0.344

AC:

29479

AN:

85772

European-Finnish (FIN)

AF:

0.575

AC:

30558

AN:

53170

Middle Eastern (MID)

AF:

0.370

AC:

2118

AN:

5726

European-Non Finnish (NFE)

AF:

0.480

AC:

523280

AN:

1090638

Other (OTH)

AF:

0.428

AC:

25489

AN:

59616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

13719

27438

41156

54875

68594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15034

30068

45102

60136

75170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.397

AC:

60273

AN:

151812

Hom.:

12926

Cov.:

AF XY:

0.400

AC XY:

29658

AN XY:

74144

show subpopulations

African (AFR)

AF:

0.246

AC:

10192

AN:

41486

American (AMR)

AF:

0.363

AC:

5537

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.411

AC:

1426

AN:

3468

East Asian (EAS)

AF:

0.262

AC:

1354

AN:

5166

South Asian (SAS)

AF:

0.324

AC:

1562

AN:

4816

European-Finnish (FIN)

AF:

0.582

AC:

6107

AN:

10490

Middle Eastern (MID)

AF:

0.346

AC:

101

AN:

292

European-Non Finnish (NFE)

AF:

0.484

AC:

32825

AN:

67828

Other (OTH)

AF:

0.382

AC:

805

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1821

3642

5463

7284

9105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.442

Hom.:

28790

Bravo

AF:

0.370

Asia WGS

AF:

0.303

AC:

1055

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.9

(source)

DANN

Benign

0.45

PhyloP100

-0.26

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over